Many patients who receive surgery or experience a major illness or injury require additional care and supervision following such surgery or illness. Patients who receive surgery or experience a major illness or injury such as hip fracture may have prolonged recovery times due to deconditioning, a bed-rest associated syndrome comprising, e.g.: decreased cardiac output, hypotension, muscular atrophy and acute muscle loss, and joint contractures (Hoenig and Rubenstein, Journal of the American Geriatrics Society, 39, 220-221. (1991)). In the elderly the loss of muscle mass and function as a result of illness or immobilization may be up to 5% per day at bedrest. Among the elderly in particular, deconditioning associated with acute illness is believed to lead to recovery times far in excess of that expected for the acute illness itself. In addition to prolonged recovery times, functional losses may result from deconditioning, the acute illness itself, and untoward effects of treatment. Although many functional losses are often reversible with activity and exercise interventions, recovery times may vary widely (Vorhies and Riley, Clinical Geriatric Medicine, 9, 745-763 (1993)). There are direct and indirect costs associated with both the acute illness and recovery periods. These costs may be considerable.
As a result of their deconditioned physical state, patients who had once been able to live independently may require additional assistance and care. In particular, patients who had previously lived independently in a private home or apartment may find that following surgery or a major illness or injury they require the formal care provided by an assisted living center, a nursing home, a rehabilitation hospital/center, an acute care hospital or a chronic medical care center.
This increase in the degree of care which is required by an individual following such deconditioning imposes increased financial costs. Moreover, such restrictions in their lifestyle may impose detrimental psychological impact with respect to the patient's self esteem and independence.
Many patients suffering from acute deconditioning, such as following a hip fracture, never regain their premorbid level of function. The recovery of a patient following a hip fracture as represented by their independent living status is generally a very difficult process. Data on the percentage of patients living independently following a hip fracture has been presented (Jette, et al., Arch. Phys. Med. Rehab., 68:735 (1987)). Approximately 48% of the patients studied were living independently prior to their hip fracture. Immediately following reconstructive hip surgery only about 5% were living independently; at 3 months and at 6 months after their hip fracture only about 25% were living independently; and at 12 months after their hip fracture only about 22% were living independently.
Very few compounds are known in the art to be useful for the enhancing the return of patients to independent living status following deconditioning. Moreover, these therapeutic regimens suffer from numerous problems and a more effective, physiological way to enhance the return of patients to independent living status following deconditioning would be highly desirable.
Growth hormone, which is secreted from the pituitary, stimulates growth of all tissues of the body that are capable of growing. In addition, growth hormone is known to have the following basic effects on the metabolic processes of the body: (1) Increased rate of protein synthesis in all cells of the body; (2) Decreased rate of carbohydrate utilization in cells of the body; (3) Increased mobilization of free fatty acids and use of fatty acids for energy.
Various ways are known to release growth hormone. For example, chemicals such as arginine, L-3,4-dihydroxyphenylalanine (L-DOPA), glucagon, vasopressin, and insulin induced hypoglycemia, as well as activities such as sleep and exercise, indirectly cause growth hormone to be released from the pituitary by acting in some fashion on the hypothalamus perhaps either to decrease somatostatin secretion or to increase the secretion of the known growth hormone secretagogue growth hormone releasing factor (GRF) or an unknown endogenous growth hormone-releasing hormone or all of these.
In cases where increased levels of growth hormone were desired, the problem was generally solved by providing exogenous growth hormone or by administering GRF, IGF-I or a peptidal compound which stimulated growth hormone production and/or release. In either case the peptidyl nature of the compound necessitated that it be administered by injection. Initially the source of growth hormone was the extraction of the pituitary glands of cadavers. This resulted in a very expensive product and carried with it the risk that a disease associated with the source of the pituitary gland could be transmitted to the recipient of the growth hormone. Recombinant growth hormone has become available which, while no longer carrying any risk of disease transmission, is still a very expensive product which must be given by injection or by a nasal spray. In addition, administration of exogenous growth hormone may result in side-effects, including edema, and does not correlate with the pulsitile release seen in the endogenous release of growth hormone.
Certain compounds have been developed which stimulate the release of endogenous growth hormone. Peptides which are known to stimulate the release of endogenous growth hormone include growth hormone releasing hormone, the growth hormone releasing peptides GHRP-6 and GHRP-1 (described in U.S. Pat. No. 4,411,890, PCT Patent Pub. No. WO 89/07110, and PCT Patent Pub. No. WO 89/07111) and GHRP-2 (described in PCT Patent Pub. No. WO 93/04081), as well as hexarelin (J. Endocrinol Invest., 15(Suppl 4), 45 (1992)). Other compounds possessing growth hormone secretagogue activity are disclosed in the following: U.S. Pat. No. 3,239,345; U.S. Pat. No. 4,036,979; U.S. Pat. No. 4,411,890; U.S. Pat. No. 5,206,235; U.S. Pat. No. 5,283,241; U.S. Pat. No. 5,284,841; U.S. Pat. No. 5,310,737; U.S. Pat. No. 5,317,017; U.S. Pat. No. 5,374,721; U.S. Pat. No. 5,430,144; U.S. Pat. No. 5,434,261; U.S. Pat. No. 5,438,136; U.S. Pat. No. 5,494,919; U.S. Pat. No. 5,494,920; U.S. Pat. No. 5,492,916; U.S. Pat. No. 5,536,716; EPO Patent Pub. No. 0,144,230; EPO Patent Pub. No. 0,513,974; PCT Patent Pub. No. WO 94/07486; PCT Patent Pub. No. WO 94/08583; PCT Patent Pub. No. WO 94/11012; PCT Patent Pub. No. WO 94/13696; PCT Patent Pub. No. WO 94/19367; PCT Patent Pub. No. WO 95/03289; PCT Patent Pub. No. WO 95/03290; PCT Patent Pub. No. WO 95/09633; PCT Patent Pub. No. WO 95/11029; PCT Patent Pub. No. WO 95/12598; PCT Patent Pub. No. WO 95/13069; PCT Patent Pub. No. WO 95/14666; PCT Patent Pub. No. WO 95/16675; PCT Patent Pub. No. WO 95/16692; PCT Patent Pub. No. WO 95/17422; PCT Patent Pub. No. WO 95/17423; PCT Patent Pub. No. WO 95/34311; PCT Patent Pub. No. WO 96/02530; PCT Patent Pub. No. WO 96/05195; PCT Patent Pub. No. WO 96/15148; PCT Patent Pub. No. WO 96/22782; PCT Patent Pub. No. WO 96/22997; PCT Patent Pub. No. WO 96/24580; PCT Patent Pub. No. WO 96/24587; PCT Patent Pub. No. WO 96/35713; PCT Patent Pub. No. WO 96/38471; PCT Patent Pub. No. WO 97/00894; PCT Patent Pub. No. WO 97/06803; PCT Patent Pub. No. WO 97/07117; Science 260, 1640-1643 (Jun. 11, 1993); Ann. Rep. Med. Chem., 28,177-186 (1993); Bioorg. Med. Chem. Ltrs., 4(22), 2709-2714 (1994); and Proc. Natl. Acad. Sci. USA 92, 7001-7005 (July 1995). Additional compounds with growth hormone secretagogue activity are described herein.